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Molecular Markers of Therapy-Resistant Glioblastoma and Potential Strategy to Combat Resistance

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Molecular Markers of Therapy-Resistant Glioblastoma and Potential Strategy to Combat Resistance International Journal of Molecular Sciences Review Molecular Markers of Therapy-Resistant Glioblastoma and Potential Strategy to Combat Resistance Ha S. Nguyen 1,2, Saman Shabani 1, Ahmed J. Awad 1,3, Mayank Kaushal 1 ID and Ninh Doan 1,4,* 1 Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA; [email protected] (H.S.N.); [email protected] (S.S.); [email protected] (A.J.A.); [email protected] (M.K.) 2 Faculty of Neurosurgery, California Institute of Neuroscience, Thousand Oaks, CA 91360, USA 3 Faculty of Medicine and Health Sciences, An-Najah National University, Nablus 11941, Palestine 4 Department of Neurosurgery, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36688, USA * Correspondence: [email protected] Received: 24 May 2018; Accepted: 13 June 2018; Published: 14 June 2018 Abstract: Glioblastoma (GBM) is the most common primary malignant tumor of the central nervous system. With its overall dismal prognosis (the median survival is 14 months), GBMs demonstrate a resounding resilience against all current treatment modalities. The absence of a major progress in the treatment of GBM maybe a result of our poor understanding of both GBM tumor biology and the mechanisms underlying the acquirement of treatment resistance in recurrent GBMs. A comprehensive understanding of these markers is mandatory for the development of treatments against therapy-resistant GBMs. This review also provides an overview of a novel marker called acid ceramidase and its implication in the development of radioresistant GBMs. Multiple signaling pathways were found altered in radioresistant GBMs. Given these global alterations of multiple signaling pathways found in radioresistant GBMs, an effective treatment for radioresistant GBMs may require a cocktail containing multiple agents targeting multiple cancer-inducing pathways in order to have a chance to make a substantial impact on improving the overall GBM survival. Keywords: glioblastoma; acid ceramidase; acid ceramidase inhibitors; carmofur; radioresistance; radiation; sphingosine; sphingosine-1-phosphate; S1P 1. Introduction Glioblastoma (GBM) is the most common primary malignant tumor of the central nervous system. With its overall dismal prognosis, GBMs demonstrate a resounding resilience against all current treatment modalities. The estimated overall survival of GBM patients is less than 1.5 years, and the 5-year survival rate is 5% [1–3]. The median age of diagnosis of GBM has increased to 64 years over the last decades, and the top incidence is 15.24/100,000 populations diagnosed within the age range of 75–84 years [1–3]. While radiation is the only proved cause of GBM, only a minority of patients develop GBMs following exposure to radiation [4]. The etiology of GBM remains to be discovered, and fewer than 5% of patients have a germline mutation which increases the risk for developing GBMs [5,6]. Symptoms at presentation are based on the location of GBMs. Eloquent-area tumors often engender symptoms ranging from numbness, weakness, and visual disturbance to language deficits, while tumors in other areas (including the non-dominant frontal and temporal lobes or the corpus callosum) may induce non-specific symptoms (such as seizures, which can be controlled with anticonvulsant medications in 25% of patients with newly diagnosed GBMs [7]). However, new Int. J. Mol. Sci. 2018, 19, 1765; doi:10.3390/ijms19061765 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2018, 19, 1765 2 of 23 emerging data have suggested that the administration of anticonvulsants may not be beneficial and can produce significant, undesired effects in GBM patients without seizures [8,9]. The presenting symptoms include headaches (~60%), memory loss (~40%), and cognitive, language, or motor deficits (~40%) [10]. The most common imaging modality to diagnose GBMs is magnetic resonance imaging (MRI) of the brain with and without gadolinium contrast. A heterogeneous ring-enhancement with area of central necrosis is the signature feature of GBMs; infrequently, GBMs can be multi-focal. Headache has been attributed to peritumoral edema, which can cause a major midline shift or mass effect [11]. Steroids such as dexamethasone are commonly employed to provide relief from headache or deficits by reducing the peritumoral edema, generally within 48 h [12,13]. Another therapy aimed at reducing the peritumoral edema is based on the anti-angiogenesis antibody bevacizumab, but it has been shown not to affect the overall survival in patients with newly diagnosed GBMs [14,15]. GBMs having certain prognostic biomarker mutations, such as isocitrate dehydrogenase (IDH), may present, on MRI, with characteristic features, such as a large non-enhancing mass with pial invasion, decreased blood flow, minimal edema and necrosis, and a tendency for the frontal and temporal lobes [16,17]. Following surgery, resected GBM tissues are formalin-fixed and paraffin-embedded prior to undergoing histopathology examinations, which characteristically show palisading necrosis, marked pleomorphism, a high mitotic index, and microvascular proliferation. Additionally, these GBM tissues are also further examined by immunostaining or sequencing for IDH mutations, O6-methylguanine methyltransferase (MGMT) methylation, and other prognostic biomarkers, which will be discussed in detail below [18,19]. The absence of a major progress in the treatment of GBM may be a result of our poor understanding of both GBM tumor biology and the mechanisms underlying the acquirement of treatment resistance in recurrent GBMs. Others have proposed that glioblastoma stem-like cells (GSCs), carrying the cell membrane marker CD133, may play a significant role in the resistance of this cancer to chemotherapy and radiotherapy [20–23]. The higher expression levels of CD133 have been linked to poorer prognosis [23]. Proteins or signaling pathways that maintain stemness may contribute to the development of therapy-resistant GBMs [24]. Novel druggable targets that have been reported to combat therapy-resistant GBMs include sodium pump α1 subunit, wingless-type MMTV integration site family member (Wnt)/β-catenin, sonic hedgehog/Glioma-associated oncogene (SHH/GLI), oligodendrocyte transcription factor 2(OLIG2), polycomb group RING finger protein 4 (BMI1), NANOG, and inhibitor of differentiation/DNA binding (ID1)[24,25]. More recently, circular RNAs (circRNAs) such as circSMARCA5, whose expression is downregulated in GBM samples as compared to control tissues, has been described to function as a novel tumor-suppressor, regulating the migration of GBM cells by modulating the oncoprotein that modulates cell migration, called RNA binding protein serine- and arginine-rich splicing factor 1 (SRSF1) [26]. A comprehensive understanding of established prognostic markers is mandatory for the development of treatments against therapy-resistant GBMs. In addition to discuss the established prognostic markers, this review also provides an overview of a novel marker called acid ceramidase (ASAH1) and its implications in the development of radioresistant GBMs. Multiple signaling pathways were found altered in radioresistant GBMs. Given the global alterations of multiple signaling pathways found in radioresistant GBMs, an effective treatment targeting radioresistant GBMs may require a cocktail containing multiple agents targeting multiple cancer-inducing pathways in order to have a chance to make a substantial impact on improving overall GBM survival. 2. O6-Methylguanine Methyltransferase (MGMT) Alkylating agents, such as temozolomide (TMZ), attach an alkyl group to the DNA, frequently at the N-7 or O-6 positions of guanine residues (Figure1)[ 27]. This process damages the DNA and triggers cell cycle death, unless the DNA is promptly repaired. O6-methylguanine methyltransferase (MGMT), a DNA repair protein, can hydrolyze the alkyl groups off guanine and impede the effectiveness of such chemotherapeutic agents [28]. Methylation of the MGMT promoter at CpG sites can suppress Int. J. Mol. Sci. 2018, 19, x FOR PEER REVIEW 3 of 21 effectivenessInt. J. Mol. Sci. of2018 such, 19, chemotherapeut 1765 ic agents [28]. Methylation of the MGMT promoter at CpG sites3 of 23 can suppress the gene and promote sensitivity to alkylating agents. Overall, up to 45–47% of GBMs exhibited methylation in prior studies [28,29]. The MGMT methylation status of tumors significantly correlatesthe gene with and progression-free promote sensitivity survival to alkylating (PFS) an agents.d overall Overall, survival up (OS) to 45–47% for patients of GBMs undergoing exhibited treatmentmethylation with in alkylating prior studies agents [28 ,[28].29]. TheFor MGMTnewly diagnosed methylation GBM, status alkylating of tumors agents significantly are a mainstay correlates optionwith progression-freeirrespective of the survival MGMT (PFS) methylation and overall stat survivalus [30]; (OS) for forelderly patients patients, undergoing those with treatment MGMT with methylationalkylating agentsmay have [28]. a Forgreater newly benefit diagnosed from TMZ GBM, monotherapy alkylating agents than are radiotherapy a mainstay option[31], while irrespective those withoutof the MGMTmethylation methylation may not status benefit [30 ];from for elderlyalklylat patients,ing agents. those At withrecurrence, MGMT alterations methylation in mayMGMT have methylationa greater benefit status fromhave TMZnot been monotherapy detected [32]; than moreover, radiotherapy the relationship [31], while with those MGMT without methylation methylation persistsmay
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